Project Summary We seek, in this revision of our renewal application, to build on the findings of our productive first project period that was focused on advancing our understanding of risk and protective factors for, and the consequences of, Alcohol Use Disorder (AUD). In the next funding period, we will apply our epidemiological and methodological expertise to examine the following facets of AUD: the etiology and consequences of its phenotypic heterogeneity; the influence of specific causal factors; the nature and etiology of the medical consequences of AUD; the transmission of AUD within marital pairs, nuclear families and extended pedigrees and the impact of acculturation on risk for AUD in various immigrant groups. These goals all utilize the wide range of data available from multiple nationwide data sources in Sweden on 11.8 million men and women, 26% of whom are 1st- or 2nd-generation immigrants. These data are of unparalleled completeness and depth and have recently been expanded to include a Swedish primary care registry (PCR) created by our team. Our first specific aim seeks to address the important problem of the heterogeneity of AUD by applying latent class analysis to develop an optimal typology of AUD in all affected cases in Sweden. We will then validate this using a split-half design and determine how these subtypes are associated with key risk factors and whether subtypes are differentially associated with psychosocial and medical sequelae of AUD. Our second aim uses standard and newly developed methods of causal inference to examine the impact of poor academic achievement on AUD risk, and evaluate, in two different ways, promising models for the psychological transmission of AUD within families. We will here utilize a range of natural experiments available in Swedish registry data. Our third aim will capitalize on the newly available PCR and other medical registers to determine the temporal, genetic, and environmental relationships between AUD and both classical alcohol-related medical complications and common medical morbidities such as cardiovascular illness, hypertension and obesity. Our fourth aim will explore the transmission of AUD risk within large pedigrees and marital relationships using three major strategies: advanced SEM methods; exploration within three-generation pedigrees of features of second generation members who do versus do not transmit AUD to the third generation; and study of the multiple ways in which various marital outcomes can impact on the risk for and the course of AUD. Our final aim will examine, among immigrants to Sweden, how rates of AUD are modified by acculturation. Applying the expertise of our research groups at Virginia Commonwealth and Lund University in AUD research, social and genetic epidemiology, and causal modeling to a uniquely powerful sample, we will be able to improve risk assessment and offer insight for promising prevention/intervention targets for AUD and its consequences.